Processesand intermediatesfor preparing substitutedchromanol derivatives

ABSTRACT

The invention relates to processes for preparing a compound of the formula  
                 
 
     and the enantiomer of said compound, wherein the benzoic acid moiety is attached at position 6 or 7 of the chroman ring, and R 1 , R 2 , and R 3  are as defined herein. The invention further relates to intermediates that are useful in the preparation of the compound of formula X above.

BACKGROUND OF THE INVENTION

[0001] This invention relates to the preparation of substitutedchromanol derivatives and to intermediates useful in said preparation.The substituted chromanol derivatives that are prepared in accord withthe present invention are disclosed in U.S. patent application Ser. No.08/295,827, filed Jan. 9, 1995, entitled “Benzopyran And Related LTB₄Antagonists,” PCT international application publication number WO96/11925 (published Apr. 25, 1996), PCT international applicationpublication number WO 96/11920 (published Apr. 25, 1996), PCTinternational application publication number WO 93/15066 (published Aug.5,1993). Each of the foregoing United States and PCT internation patentapplications are incorporated herein by reference in their entirety.

[0002] The substituted chromanol derivatives that are prepared in accordwith the present invention inhibit the action of LTB₄, as disclosed inU.S. patent application Ser. No. 08/295,827, referred to above. As LTB₄antagonists, the substituted chromanol derivatives that are preparedaccording to the present invention are useful in the treatment ofLTB₄-induced illnesses such as inflammatory disorders includingrheumatoid arthritis, osteoarthritis, inflammatory bowel disease,psoriasis, eczema, erythma, pruritis, acne, stroke, graft rejection,autoimmune diseases, and asthma.

SUMMARY OF THE INVENTION

[0003] The present invention relates to a process of preparing acompound of the formula

[0004] or the enantiomer of said compound, wherein in said compound offormula X the R³-substituted benzoic acid moiety is attached at carbon 6or 7 of the chroman ring;

[0005] R¹ is —(CH₂)_(q)CHR⁵R⁶ wherein q is 0 to 4;

[0006] each R² and R³ is independently selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆ alkyl) wherein n is0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxyand —S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups;

[0007] R⁵ is H, C₁-C₆ alkyl, or phenyl substituted by R²;

[0008] R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10membered heteroaryl, wherein said aryl and heteroaryl groups areoptionally substituted by 1 or 2 substituents independently selectedfrom phenyl, R², and phenyl substituted by 1 or 2 R²;

[0009] which comprises treating a compound of the formula

[0010] or the enantiomer of said compound of formula IX in thepreparation of the enantiomer of said compound of formula X, wherein R¹,R², and R³ are as defined above, R⁴ is C₁-C₆ alkyl, and the benzoatemoiety is attached to position 6 or 7 of the chroman ring, with a base.

[0011] In said process of preparing the compound of formula X, thecompound of formula IX is preferably treated with an aqueous hydroxidebase, R¹ is preferably benzyl, 4-fluorobenzyl, 4-phenylbenzyl,4-(4-fluorophenyl)benzyl, or phenethyl, R² is preferably hydrogen orfluoro, R³ is preferably fluoro, chloro, or methyl optionallysubstituted by 1 to 3 fluorines, and R⁴ is preferably ethyl or2,2-dimethylpropyl. Most preferably, said compound of formula IX istreated with a base comprising aqueous sodium hydroxide, said compoundof formula IX is(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester, and said compound of formula X is(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid.

[0012] In a further aspect of the present invention, said compound offormula IX, or the enantiomer of said compound, wherein R¹, R², R³, andR⁴ are as defined above, is prepared by treating a compound of theformula

[0013] or the enantiomer of said compound of formula VII in thepreparation of the enantiomer of the compound of formula IX, wherein R¹and R² are as defined above and the boronic acid moiety is attached atposition 6 or 7 of the chroman ring, with a compound of the formula

[0014] wherein R³ and R⁴ are as defined above and Z is halo or C₁-C₄perfluoroalkylsulfonate, in the presence of a base or fluoride salt anda palladium catalyst.

[0015] In said process of making the compound of formula IX, or theenantiomer of said compound, preferred substituents for R¹, R², R³ andR⁴ are as stated above for said process of making the compound offormula X. In another preferred embodiment, Z is halo, the base orfluoride salt is selected from sodium carbonate, triethylamine, sodiumbicarbonate, cesium carbonate, tripotassium phosphate, pottasiumfluoride, cesium fluoride, sodium hydroxide, barium hydroxide, andtetrabutylammonium fluoride, the palladium catalyst is selected fromtetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),and 10% palladium on carbon. Most preferably, the base or fluoride saltis potassium fluoride, the palladium catalyst is 10% palladium oncarbon, the compound of formula VII is(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid, and the compoundof formula VIII is ethyl 2-iodo-4-trifluoromethyl-benzoate.

[0016] In a further aspect of the invention, the compound of formulaVII, or the enantiomer of said compound, wherein R¹ and R² are asdefined above, is prepared by treating a compound of the formula

[0017] or the enantiomer of said compound of formula VI in thepreparation of the enantiomer of the compound of formula VII, wherein R¹and R² are as defined above and X is a halide and is attached atposition 6 or 7 of the chroman ring, with (1) C₁-C₄ alkyl lithium, and(2) a borating agent.

[0018] In said process of making the compound of formula VII, or theenantiomer of said compound, preferred substituents for R¹ and R² are asstated above for said process of making the compound of formula X. Inanother preferred embodiment, X is bromo or iodo, and said compound offormula VI is treated with (1) methyl lithium, (2) butyl lithium, and(3) said borating agent which is selected from borane-tetrahydrofurancomplex, triisopropyl borate, and trimethyl borate. Most preferably, thecompound of formula VI is (3S,4R)-3-benzyl-7-bromo-chroman-4-oland saidborating agent is borane-tetrahydrofuran complex.

[0019] In a further aspect of the invention, the compound of formula VI,or the enantiomer of said compound, wherein R¹, R² and X are as definedabove, is prepared by treating a compound of the formula

[0020] or the enantiomer of said compound of formula V in thepreparation of the enantiomer of the compound of formula VI, wherein R¹,R² and X are as defined above and X is attached at position 4 or 5 ofthe phenyl ring, and Y is halo or nitro, with a base, optionally in thepresence of added copper salts.

[0021] In said process of making the compound of formula VI, or theenantiomer of said compound, preferred substituents for R¹, R² and X areas stated above for said process of making the compound of formula VII.In another preferred embodiment, Y is halo, and said base is potassiumtert-butoxide, sodium bis(trimethylsilyl)amide, potassiumbis(trimethylsilyl)amide, cesium carbonate, or sodium hydride. Mostpreferably, said base is potassium tert-butoxide and the compound offormula V is(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.

[0022] In a further aspect of the invention, the compound of formula V,or the enantiomer of said compound, wherein R¹, R², X and Y are asdefined above, is prepared by treating a compound of the formula

[0023] or the enantiomer of said compound of formula IV in thepreparation of the enantiomer of the compound of formula V, wherein R¹,R², X and Y are as defined above and X is attached at position 4 or 5 ofthe phenyl ring, and X_(c) is a chiral auxiliary, with a hydridereducing agent.

[0024] In said process of making the compound of formula V, or theenantiomer of said compound, preferred substituents for R¹, R², X and Yare as stated above for said process of making the compound of formulaVI. In another preferred embodiment, X_(c) is(R)-4-benzyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone,(4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one, or(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one, wherein said X_(c) isattached at the nitrogen of the oxazolidin-2-one ring, and said reducingagent is lithium borohydride, lithium aluminum hydride, sodiumborohydride, or calcium borohydride. Most preferably, the compound offormula IV is[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate or[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,and said reducing agent is lithium borohydride.

[0025] In a further aspect of the invention, the compound of formula IV,or the enantiomer of said compound, wherein R¹, R², X, X_(c) and Y areas defined above, is prepared by treating a compound of the formulaR¹—CH₂C(O)—X_(c) wherein R¹ and X_(c) are as defined above, with (1) aLewis acid, (2) a base, and (3) a compound of formula

[0026] wherein R², X and Y are as defined above and X is attached atposition 4 or 5 of the phenyl ring.

[0027] In said process of making the compound of formula IV, or theenantiomer of said compound, preferred substituents for R¹, R², X, X_(c)and Y are as stated above for said process of making the compound offormula V. In another preferred embodiment, said Lewis acid is a boronhalide or sulfonate, and said base is triethylamine ordiisopropylethylamine. Most preferably, said compound of formulaR¹—CH₂C(O)—X_(c) is(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one, said compound offormula III is 4-bromo-2-fluoro-benzaldehyde, said Lewis acid isdibutylboron triflate, and said base is triethylamine.

[0028] In a further aspect of the invention, the compound of formula IV,or the enantiomer of said compound, wherein R¹, R², X, X_(c) and Y areas defined above, is prepared by treating a compound of the formulaR¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are as defined above, with (1) atitanium(IV) halide, (2) a base optionally followed by treatment with adonor ligand, and (3) a compound of formula

[0029] wherein R², X and Y are as defined above and X is attached atposition 4 or 5 of the phenyl ring.

[0030] In said process of making the compound of formula IV, or theenantiomer of said compound, preferred substituents for R¹, R², X, X_(c)and Y are as stated above for said process of making the compound offormula V. In another preferred embodiment, said titanium(IV) halide istitanium tetrachloride, and said base is a tertiary amine or tertiarydiamine base. In another preferred embodiment, said base istriethylamine or N,N,N′,N′-tetramethylethylenediamine, and saidtreatment with said base is followed by treatment with a donor ligandselected from 1-methyl-2-pyrrolidinone, dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate,and 2,2′-dipyridyl. Most preferably, said compound of formulaR¹CH₂C(O)—X_(c) is (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one,said compound of formula III is 4-bromo-2-fluoro-benzaldehyde, said baseis N,N,N′,N′-tetramethylethylenediamine, and said donor ligand is1-methyl-2-pyrrolidinone.

[0031] In a further aspect of the invention, said compound of formulaIX, or the enantiomer of said compound, wherein R¹, R², R³ and R⁴ are asdefined above, is prepared by coupling a compound of the formula

[0032] or the enantiomer of said compound in the preparation of theenantiomer of the compound of formula IX, wherein R¹ and R² are asdefined above and X′, which is attached at position 6 or 7 of thechroman ring, is halo or C₁-C₄ perfluoroalkylsulfonate, with a compoundof the formula

[0033] wherein R³ and R⁴ are as defined above, in the presence of a baseor fluoride salt and a palladium catalyst.

[0034] In the process of preparing the compound of formula IX, or theenantiomer of said compound, as recited directly above, preferredsubstituents for R¹, R², R³ and R⁴ are as stated above for the processof making the compound of formula X. In another preferred embodiment, X′is preferably bromo, iodo, or trifluoromethanesulfonate, the palladiumcatalyst is preferably selected fromtetrakis(triphenylphosphine)palladium(O),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),and 10%palladium on carbon, and the base or fluoride salt is selectedfrom sodium carbonate, triethylamine, sodium bicarbonate, cesiumcarbonate, tripotassium phosphate, pottasium fluoride, cesium fluoride,sodium hydroxide, barium hydroxide, and tetrabutylammonium fluoride.Most preferably, the compound of formula VI is(3S,4R)-3-benzyl-7-bromo-chroman-4-ol, the compound of formula XIV is2-(2,2-dimethyl-propoxycarbonyl-5-trifluoromethyl-benzeneboronic acid,the base or fluoride salt is sodium carbonate, and the palladiumcatalyst is tetrakis(triphenylphosphine)palladium(0).

[0035] In a further aspect of the invention, the compound of formulaXIV, wherein R³ and R⁴ are as defined above, is prepared by hydrolyzinga compound of the formula

[0036] wherein R³ and R⁴ are as define above, the dashed line indicatesa bond or no bond between the B and N atoms, n and m are independently 2to 5, and R⁸ is H or C₁-C₆ alkyl. R⁸ is preferably H and preferredsubstituents for R³ and R⁴ are as stated above for said process ofmaking a compound of formula X. Preferably, said hydrolysis is effectedwith an acid, such as hydrochloric acid, and n and m are each 2. Mostpreferably, said compound of formula XVI is2-[1,3,6,2)dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester.

[0037] In a further aspect of the invention, the compound of formulaXVI, wherein R³, R⁴ and R⁸ are as defined above, is prepared by reactinga compound of formula XIV, wherein R³ and R⁴ are as defined above, witha compound of formula HO(CH₂)_(m)—N(R⁸)—(CH₂)_(n)OH (formula XV),wherein n, m and R⁸ are as defined above. In said process of preparingthe compound of formula XVI, preferred substituents for R³ and R⁴ are asstated above for said process of preparing a compound of formula X. Mostpreferably, said compound of formula XIV is2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acidand said compound of formula XV is diethanolamine.

[0038] In a further aspect of the invention, the compound of formulaXIV, wherein R⁴ and R³ are as defined above, is prepared by hydrolyzinga compound of the formula

[0039] wherein R³ and R⁴ are as defined above and R⁷ is C₁-C₆ alkyl.Said hydrolysis is preferably effected with an acid, such ashydrochloric acid. Preferred substituents for R³ and R⁴ are as statedabove for said process of making a compound of formula X.

[0040] In a further aspect of the invention, the compound of formulaXIII, wherein R³, R⁴ and R⁷ are as defined above, is prepared bytreating a compound of the formula

[0041] wherein R³ and R⁴ are as defined above, with a metal amide basein the presence of a tri-(C₁-C₆ alkyl)borate.

[0042] In said process of making the compound of formula XIII, preferredsubstituents for R³ and R⁴ are as stated above for said process ofmaking the compound of formula X. In another preferred embodiment, saidmetal amide base is selected from lithium diisopropylamide, lithiumdiethylamide, lithium 2,2,6,6-tetramethylpiperidine, andbis(2,2,6,6-tetramethylpiperidino)magnesium, and said tri-(C₁-C₄alkyl)borate is selected from triisopropylborate, triethylborate, andtrimethylborate. Most preferably, the compound of formula XII is4-trifluoromethyl-benzoic acid 2,2-dimethyl-propyl ester, said metalamide base is lithium diisopropylamide, and said tri-(C₁-C₆ alkyl)borateis triisopropylborate.

[0043] In a further aspect of the invention, the compound of formula X,or the enantiomer of said compound, wherein R¹, R², and R³ are asdefined above, is reacted with a secondary amine of the formula NHR⁵R⁶,wherein R⁵ and R⁶ are as defined above, to form an ammonium carboxylateof the formula

[0044] or the enantiomer of said compound of formula XVII, wherein R¹,R², R³, R⁵ and R⁶ are as defined above. Preferred substituents for R¹,R², and R³ are as stated above for said process of making a compound offormula X. In said secondary amine, R⁵ and R⁶ are each preferablycyclohexyl. Most preferably, said compound of formula XVII is(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethylbenzoate.

[0045] The invention also relates to a process of preparing a compoundof the formula

[0046] or the enantiomer of said compound, wherein R¹ and X_(c) are asdefined above for said process of preparing a compound of formula V, andR¹¹ is C₁-C₉ alkyl, C₂-C₉ alkenyl or phenyl substituted by Y in the 2position, X in the 4 or 5 position, and R² in one of the remainingpositions of the phenyl moiety, wherein Y, X and R² are as defined abovefor said process of preparing a compound of formula V, by treating acompound of the formula R¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are asdefined above, with (1) a titanium(IV) halide, (2) a base optionallyfollowed by treatment with a donor ligand, and (3) less than 2equivalents, preferably about 1 equivalent, of a compound of the formulaR¹¹—C(O)H, wherein R¹¹ is as defined above, relative to the amount ofsaid compound of formula R¹—CH₂C(O)—X_(c). Preferred substituents andreagents for said process of preparing said compound of formula XIX, orthe enantiomer of said compound, are as stated above for said process ofpreparing a compound of formula IV using said titanium(IV) halide.

[0047] The invention also relates to a compound of the formula

[0048] and to the enantiomer of said compound, wherein R¹, R², X and Yare as stated above for said process of preparing a compound of theformula VI.

[0049] In said compound of formula V, and the enantiomer of saidcompound, preferred substituents for R¹, R², X and Y are as stated abovefor said process of preparing a compound of the formula VI. Mostpreferably, said compound of formula V is(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol.

[0050] The invention also relates to a compound of the formula

[0051] and to the enantiomer of said compound, wherein R¹ and R² are asstated above for said compound of formula V and X′ is halo or C₁-C₄perfluoroalkylsulfonate and is attached at position 6 or 7 of thechroman ring.

[0052] In said compound of formula VI, and the enantiomer of saidcompound, preferred substituents for R¹ and R² are as stated above forsaid compound of formula V, and X′ is preferably bromo, iodo, ortrifluoromethanesulfonate. Most preferably, said compound of the formulaVI is (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

[0053] The invention also relates to a compound of the formula

[0054] and to the enantiomer of said compound, wherein R¹ and R² are asstated above for said compound of formula VI.

[0055] In said compound of formula VII, and the enantiomer of saidcompound, preferred substituents for R¹ and R² are as stated above forsaid compound of formula VI. Most preferably, said compound of theformula VII is (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid.

[0056] The invention also relates to a compound of the formula

[0057] and to the enantiomer of said compound, wherein R¹, R², R³ and R⁴are as stated above for said process of preparing a compound of theformula X and the benzoate moiety is attached to position 6 or 7 of thechroman ring.

[0058] In said compound of formula IX, and the enantiomer of saidcompound, preferred substituents for R¹, R², R³ and R⁴ are as statedabove for said process of preparing a compound of the formula X. Mostpreferably, the compound of formula IXis(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoiecid ethylester.

[0059] The invention also relates to a compound of the formula

[0060] wherein R³, R⁴ and R⁷ are as stated above for said process ofpreparing a compound of the formula XIV using a compound of formulaXIII.

[0061] In said compound of formula XIII, preferred substituents for R⁷,R³ and R⁴ are as stated above for said process of preparing a compoundof the formula XIV using a compound of formula XIII.

[0062] The invention also relates to a compound of the formula

[0063] wherein R³ and R⁴ are as stated above for said compound offormula XIII.

[0064] In said compound of formula XIV, preferred substituents for R³and R⁴ are as stated above for said compound of formula XIII. Mostpreferably, said compound of the formula XIV is2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid.

[0065] The invention also relates to compounds of the formula

[0066] wherein the dashed line indicates a bond or no bond between the Band N atoms, n and m are independently 2 to 5, R³ and R⁴ are as definedabove for said compound of formula XIV, and R⁸ is H or C₁-C₆ alkyl.

[0067] In said compound of formula XVI, n and m are each preferably 2,preferred substituents for R³ and R⁴ are as defined above for saidcompound of formula XIV, and R¹¹ is preferably H. Most preferably, thecompound of formula XVI is2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoicacid2,2-dimethyl-propyl ester.

[0068] The invention also relates to an ammonium carboxylate compound ofthe formula

[0069] and to the enantiomer of said compound, wherein R¹, R², R³, R¹and R⁶ are as defined above for said process of preparing a compound ofthe formula X. Preferred substituents for R¹, R², and R³ are as statedabove for said process of making a compound of formula X. In theammonium moiety, R⁵ and R⁶ are each preferably cyclohexyl. Mostpreferably, said compound of formula XVII is(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethylbenzoate.

[0070] The present invention also relates to a compound of the formula

[0071] and to the enantiomer of said compound, wherein R¹, R², X, Y andX_(c) are as defined above for said process of preparing a compound offormula V. The present invention also relates to solvates of saidcompound of formula IV and the enantiomer of said compound of formulaIV. Preferred solvates of said compound of formula IV, and theenantiomer of said compound, are those formed with a donor ligandselected from 1-methyl-2-pyrrolidinone, dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate,and 2,2′-dipyridyl. The preferred compound of formula IV is[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,and the preferred solvate of said compound is [4R-[3 (2R,3S)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propioy]oxazolidin-2-one, 1-methyl-2-pyrrolidinone solvate.

[0072] The term “halo”, as used herein, unless otherwise indicated,means fluoro, chloro, bromo or iodo.

[0073] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof.

[0074] The term “alkoxy”, as used herein, includes O-alkyl groupswherein “alkyl” is defined above.

[0075] The term “aryl”, as used herein, unless otherwise indicated,includes an organic radical derived form an aromatic hydrocarbon byremoval of one hydrogen, such as phenyl or naphthyl.

[0076] The term “heteroaryl”, as used herein, unless otherwiseindicated, includes an organic radical derived from an aromaticheterocyclic compound by removal of one hydrogen, such as pyridyl,furyl, thienyl, isoquinolyl, pyrimidinyl, and pyrazinyl.

[0077] The term “enantiomer” as used herein in reference to the compoundof formula X

[0078] means a compound of the formula

[0079] The term “enantiomer” as used herein in reference to the compoundof formula IX

[0080] means a compound of the formula

[0081] The term “enantiomer” as used herein in reference to a compoundof formula VII

[0082] means a compound of the formula

[0083] The term “enantiomer” as used herein in reference to a compoundof the formula VI

[0084] means a compound of the formula

[0085] The term “enantiomer” as used herein in reference to a compoundof the formula V

[0086] means a compound of the formula

[0087] The term “enantiomer” as used herein in reference to a compoundof the formula IV

[0088] means a compound of the formula

[0089] The term “enantiomer” as used herein in reference to a compoundof the formula XVII

[0090] means a compound of the formula

[0091] The term “enantiomer” as used herein in reference to a compoundof the formula XIX

[0092] means a compound of the formula

DETAILED DESCRIPTION OF THE INVENTION

[0093] The process of the present invention and the preparation of thecompounds of the present invention are illustrated in the followingSchemes. In the following Schemes and discussion that follows, unlessotherwise indicated, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, Y, Z, X,X_(c), and X′ are as defined above. The following Schemes and thediscussion that follows describe the preparation of the compounds offormulas I-XIX. The following Schemes and description that follows alsoapplies to the enantiomers of the compounds of formulas 1-XIX, whereinthe term “enantiomer” is as defined above.

[0094] Overall, the synthetic sequence in Scheme I involves attachingchiral auxiliary X_(c) to R¹-containing compound I (step 1), asymmetricaldol condensation with aldehyde III (step 2 or 2′), reductive removalof the chiral auxiliary from aldol IV (step 3), base-mediatedcyclization of diol V (step 4), lithiation and boration of halochromanolVI (step 5), coupling boronic acid VII with aryl halide or sulfonate VII(step 6), and hydrolysis of ester IX (step 7).

[0095] In step 1 of Scheme 1, chiral auxiliary HX_(c) is converted tothe corresponding anion by treatment with a suitably strong base, suchas an alkyllithium base, preferably butyllithium, in an aprotic solvent,such as an ethereal solvent, preferably tetrahydrofuran (THF), at atemperature of approximately −80 to 0° C., preferably −78 to −55° C.,over a period of about 20 minutes to one hour. Substituent X_(c) is achiral auxiliary that is suitable to control relative and absolutestereochemistry in asymmetric aldol reactions. Examples of HX_(c)include (R)-4-benzyl-2-oxazolidinone,(S)-4-benzyl-2-oxazolidinone,(4R,5S)-4-methyl-5-phenyl-oxazolidin-2-one, and(4S,5R)-4-methyl-5-phenyl-oxazolidin-2-one. The resulting anion istreated with acylating agent 1, wherein group W is a halide, preferablychloride, and R¹ is as defined above, in the same solvent at atemperature of approximately −80 to 0° C., preferably about −75° C.,over a period of about one hour, and then warmed to approximately −20 to20° C., preferably about 0° C., before aqueous workup, which ispreferably done by treatment with aqueous sodium bicarbonate, to yieldacylated chiral auxiliary II.

[0096] Step 2 of Scheme 1 is an “Evans aldol” reaction that is performedunder conditions that are analogous to those described in Evans, D. A.;Bartroli, J.; Shih, T. L., J. Am. Chem. Soc. 1981, 103, 2127 and Gage,J. R.; Evans, D. A., Org. Syn. 1989, 68, 83, both of which referencesare incorporated herein by reference. In particular, in step 2 of Scheme1, the acylated chiral auxiliary II is treated with a Lewis acid, abase, and substituted benzaldehyde III to yield alcohol IV with a highdegree of stereoselectivity. Benzaldehyde III is substituted with orthosubstituent Y which serves as a leaving group during cyclization step 4,group X (or X′ for Scheme 2, in particular coupling step 4 of Scheme 2)which is substituted by the aryl sidechain during coupling step 6, andsubstituent R² which is as defined above. Substituent X (or X′ forScheme 2) is attached at position 4 or 5 of the phenyl moiety ofbenzaldehyde III. The leaving group Y is typically a halo or nitro groupand X is a halide (and, for Scheme 2, X′ is a halide or C₁-C₄perfluoroalkylsulfonate). To prepare aldol product IV, acylated chiralauxiliary II is treated with a boron halide or sulfonate, such as adialkylboron sulfonate, preferably dibutylboron triflate, in an aproticsolvent, such as dichloromethane, 1,2-dichloroethane, toluene, ordiethyl ether, preferably dichloromethane, at a temperature of about −78to 40° C., preferably −5° C., over a period of about 20 minutes,followed by treatment with a tertiary amine base, such as triethylamineor diisopropylethylamine, preferably triethylamine, at a temperature ofabout −78 to 40° C., preferably −5 to 5° C., over a period of about onehour. This mixture is treated with substituted benzaldehyde III at atemperature of about −100 to 0° C., preferably about −70° C., over aperiod of about 30 minutes. This mixture is allowed to warm to atemperature of about −20 to 25° C., preferably about −10° C., over aperiod of about one hour, and then treated with a protic oxidativequench, preferably by the successive addition of a pH 7 buffer solution,methanol, and aqueous hydrogen peroxide, at a temperature of less thanabout 15° C., to yield alcohol IV.

[0097] Step 2′ of Scheme 1 is an alternative, and preferable, method ofproviding alcohol IV using a titanium-containing Lewis acid. In step 2′of Scheme 1, acylated chiral auxiliary II is treated with a titanium(IV)halide, preferably titanium tetrachloride, in an aprotic solvent such asdichloromethane, 1,2-dichloroethane, or toluene, preferablydichloromethane, at a temperature of about −80 to 0° C., preferably −80to −70° C., over a period of about 30 minutes with additional stirringfor about 30 minutes, followed by treatment with a tertiary amine ortertiary diamine base, such as triethylamine orN,N,N′,N′-tetramethylethylenediamine, preferablyN,N,N′,N′-tetramethylethylenediamine, at a temperature of about −80 to0° C., preferably −80 to −65° C., over a period of about 30 minutes.This is optionally, and preferably, followed by treatment with a donorligand, such as 1-methyl-2-pyrrolidinone, dimethylformamide,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, triethylphosphate,or 2,2′-dipyridyl, preferably 1-methyl-2-pyrrolidinone, at a temperatureof about −80 to 0° C., preferably −80 to −65° C., followed by stirringfor a period of about 30 minutes. This mixture is treated withsubstituted benzaldehyde III at a temperature of about −100 to 0° C.,preferably −80 to −65° C., over a period of about 30 minutes, andallowed to warm to a temperature of −30 to 30° C., preferably 0 to 25°C., over a period of about one to 24 hours, preferably about 4 hours.This mixture is treated with a protic quench, preferably aqueousammonium chloride, at a temperature of −30 to 30° C., preferably 0 to25° C., to yield alcohol IV. Where treatment with a donor ligand isdone, the alcohol IV is, in some cases, provided as a crystallinesolvate with the donor ligand. Stirring the quenched reaction mixturewith a solid support such as Celite® for a period of about 12 hours at atemperature of about 20° C. improves the filtration of the reactionmixture for removal of titanium byproducts.

[0098] The titanium aldol conditions of step 2′ of Scheme 1 arepreferable and operationally more simple than the boron aldol conditionsof step 2 of Scheme 1 in that they avoid the pyrophoric reagenttributylborane, the corrosive reagent triflic acid, and their exothermiccombination in the preparation of the Lewis acid dibutylboron triflate.Further, in contrast to titanium aldol reactions described in theliterature, such as in Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.;Urpi, F., J. Am. Chem. Soc. 1991, 113, 1047, the titanium aldolconditions of step 2′ of Scheme 1 provide high selectivity with lessthan two equivalents of the aldehyde III. Preferably, about oneequivalent of aldehyde III is used in this step. The phrase “about oneequivalent” as used herein in reference to aldehyde III or a compound ofthe formula R¹¹C(O)H (as recited in the claims) means less than 1.5equivalents of said compound. In the foregoing article by Evans et al.,it is reported that two equivalents of aldehyde would be required for atitanium aldol reaction analogous to step 2′ of Scheme 1.

[0099] In addition to having utility in the preparation of thetherapeutic agents of formula X, the titanium aldol conditions of step2′ of Scheme 1 are useful in the preparation of HIV protease inhibitorcompounds that are described in United Kingdom patent application number2,270,914 (published Mar. 30, 1994) and in B. D. Dorsey et al.,Tetrahedron Letters, 1993, 34(12), 1851. Scheme 4 illustrates theapplication of titanium aldol reaction to aldehyde XVIII in which R¹¹ isC₁-C₉ alkyl, C₂-C₉ alkenyl, or phenyl substituted by Y in the 2position, X in the 4 or 5 position, and R² in one of the remainingpositions of the phenyl moiety, wherein Y, X and R² are as definedabove. The reaction conditions for Scheme 4 are the same as thosedescribed above for step 2′ of Scheme 1. Aldehyde XVIII encompassesaldehyde III from Scheme 1, and alcohol XIX encompasses alcohol IV fromScheme 1. The reaction of Scheme 4 can be used to prepare the HIVprotease inhibitor compounds that are described in United Kingdom patentapplication number 2,270,914, referred to above, where R¹¹ is C₁-C₉alkyl or C₂-C₉ alkenyl, preferably 3-cyclohexylpropenyl.

[0100] Table 1 below illustrates how the product of Scheme 4 or step 2′of Scheme 1 can vary depending on the reaction conditions that are used,and, in particular, how the diastereoselectivity increases by increasingthe amount TMEDA from 1.2 to 3 equivalents and by the addition of 2equivalents of NMP. In Table 1, 1.0 equivalent of aldehyde RCHO was usedfor each reaction, x and y represent equivalents of base and NMP,respectively, NMP means 1-methyl-2-pyrrolidinone, TMEDA meansN,N,N′,N′-tetramethylethylenediamine, NEtiPr₂ meansdiisopropylethylamine, and the ratio of diastereomers was determined byHPLC. The aldol isomers were identified by separation and conversion toknown carboxylic acid isomers by hydrolysis with LiOH/H₂O₂ according toprocedures analogous to those described in Van Draanen, N. A.;Arseniyadis, S.; Crimmins, M. T.; Heathcock, C. H., J. Org. Chem. 1991,56, 2499 and Gage, J. R.; Evans, D. A., Org. Syn. 1989, 68, 83. Thedesired isomer is indicated in bold.

TABLE 1 enolization ratio of aldol RCHO x base y NMP temperaturediastereomers

1.2 NEtiPr₂ 0 NMP  0° C. 33:--:2:65 (syn:anti:syn:anti) ″ 1.2 TMEDA 0NMP  0° C. 22:--:55:23 ″ 1.2 NEtiPr₂ 0 NMP −78° C. 29:--:10:62 ″ 1.2TMEDA 0 NMP −78° C. 16:--:57:28 ″ 2 TMEDA 0 NMP −78° C. 2:--:86:11 ″ 3TMEDA 0 NMP −78° C. 2:--:94:5 ″ 3 TMEDA 2 NMP −78° C. 1:--:99:--

1.2 TMEDA 0 NMP −78° C. --:--:11:89 (anti:anti:syn:syn) ″ 3 TMEDA 2 NMP−78° C. --:--:--:100

1.2 TMEDA 0 NMP −78° C. 28:39:33:-- ″ 3 TMEDA 2 NMP −78° C. 4:92:3:2

1.2 TMEDA 0 NMP −78° C. 18:40:42:-- ″ 3 TMEDA 2 NMP −78° C. 2:96:2:--

[0101] In step 3 of Scheme 1, chiral auxiliary X_(c) is removed (andoptionally recovered for reuse in step 1), and the oxidation state ofcompound IV (acid level) is reduced to the desired alcohol V accordingto a procedure analogous to the procedure described in Penning, T. D.;Djuric, S. W.; Haack, R. A.; Kalish, V. J.; Miyashiro, J. M.; Rowell, B.W.; Yu, S. S., Syn. Commun. 1990, 20, 307, which is incorporated hereinby reference. In this process, alcohol IV is treated with a hydridereducing agent, such as lithium borohydride, lithium aluminum hydride,sodium borohydride, or calcium borohydride, preferably lithiumborohydride, in an ethereal solvent such as THF, diisopropyl ether, ormethyl tert-butyl ether, preferably THF, typically containing a proticsolvent, such as water, ethanol, or isopropanol, at a temperature ofabout −78° C. to reflux temperature, preferably 0° C. to ambienttemperature (20-25° C.). After a period of one to 24 hours, typically 12hours, the reaction is quenched with water with the optional subsequentaddition of hydrogen peroxide. Chiral auxiliary HX_(c) can be recoveredfor reuse in step 1 by selective precipitation, or by extraction ofHX_(c) into aqueous acid, preferably hydrochloric acid, from a solutionof diol V in an organic solvent such as diisopropyl ethyl or a mixtureof ethyl acetate and hexane, followed by neutralization of the aqueousacidic extracts with base, and extraction of HX_(c) into an organicsolvent.

[0102] Step 4 of Scheme 1 is an intramolecular aromatic substitutionwhereby the primary hydroxyl in diol V displaces ortho leaving group Yto generate the chromanol ring system of VI. In particular, diol V, inwhich leaving group Y is a halo or nitro group, preferably a fluorogroup, is treated with a base, such as potassium tert-butoxide, sodiumbis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, cesiumcarbonate, or sodium hydride, preferably potassium tert-butoxide, in anaprotic solvent such as THF, dimethyl sulfoxide, or1-methyl-2-pyrrolidinone, preferablyTHF, optionally in the presence ofadded copper salts, at a temperature of between ambient temperature and130° C., preferably about 70° C., for a period of one to 24 hours,typically about four hours, giving chromanol VI. In chromanol VI, thesubstituent X (or X′ for Scheme 2) is attached at position 6 or 7 of thechroman ring.

[0103] In step 5 of Scheme 1, substituent X in chromanol VI is convertedto lithium and then a boronic acid group. For lithiation, chromanol VIis preferably treated first with methyl lithium to form the lithiumalkoxide followed by butyl lithium to form the aryl lithium. In thisprocess, chromanol VI, in which X is a halide, preferably bromide oriodide, is treated with two equivalents of alkyllithium, preferablyfirst with one equivalent of methyllithium followed by one equivalent ofbutyl lithium, in an ethereal solvent, preferably THF, at a temperatureof −78 to 0° C., preferably −70 to-65° C., for a period of about onehour, followed by treatment with a borating agent, such asborane-tetrahydrofuran complex, triisopropyl borate, or trimethylborate, preferably borane-THF complex, at a temperature of −78 to 0° C.,preferably −70 to −65° C., over a period of about 30 minutes, followedby quenching with water or optionally aqueous acid at a temperature ofabout −65° C. to ambient temperature, preferably at about 0° C., givingboronic acid VII in which the boronic acid moiety is attached atposition 6 or 7 of the chroman ring.

[0104] Step 6 of Scheme 1 is a Suzuki coupling between boronic acid VIIand compound VII to form the biaryl bond of compound IX. In compoundVIII, Z is a halide or sulfonate, preferably bromide, iodide, ortrifluoromethanesulfonate, R⁴ is C₁-C₆ alkyl and R³ is as defined above.This procedure is analogous to the procedure described in Miyaura, N.;Suzuki, A., Chem. Rev. 1995, 95, 2457, which is incorporated herein byreference. This procedure is preferable to the coupling of zinc or tinspecies due to the difficulty of preparing organozincs on a large scaleand the toxicity of organotin compounds. In this process, a mixture ofboronic acid VII, arene VIII, a palladium catalyst, such astetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),or 10% palladium on carbon, preferably 10% palladium on carbon, and abase or fluoride salt, such as sodium carbonate, triethylamine, sodiumbicarbonate, cesium carbonate, tripotassium phosphate, potassiumfluoride, cesium fluoride, or tetrabutylammonium fluoride, preferablypotassium fluoride, in a solvent such as ethanol, dimethoxyethane, ortoluene, optionally containing water, preferably ethanol, are stirred ata temperature of between ambient temperature and 130° C., preferablyreflux temperature, for a period of about one to about 24 hours,preferably about three hours, giving biaryl IX in which the benzyl estermoiety is attached at position 6 or 7 of the chroman ring.

[0105] In step 7 of Scheme 1, ester IX is treated with aqueous hydroxidebase, such as aqueous sodium hydroxide, in an alcoholic solvent, such asisopropyl alcohol, at a temperature of between 40° C. and refluxtemperature, preferably reflux temperature, for a period of about one toabout 24 hours, preferably about six hours. The reaction mixture iscooled to ambient temperature and partitioned between aqueous base andan organic solvent, such as a mixture of hexane and isopropyl ether. Theaqueous solution is acidified, and the final compound X is extractedinto an organic solvent such as ethyl acetate. This method of extractingthe compound X with organic solvents removes neutral impurities which isparticularly advantageous in the last step of this synthesis.

[0106] To facilitate the handling of carboxylic acid X, this compoundcan be treated with a secondary amine of the formula NHR⁵R⁶, wherein R⁵and R⁶ are as defined above, in a solvent such as toluene, to form anammonium carboxylate of the formula

[0107] wherein R¹, R², R³, R⁵ and R⁶ are as defined above. Ammoniumcarboxylate XVII can be treated with an aqueous acid such a hydrochloricacid or sulphuric acid, preferably hydrochloric acid, in a solvent suchas ethyl acetate, toluene, or methylene chloride, preferably ethylacetate, at a temperature ranging from 0° C. to ambient temperature fora period of 30 minutes to 3 hours, preferably 1 hour, to providecarboxylic acid X.

[0108] Scheme 2 illustrates an alternative to the coupling sequence ofsteps 5 and 6 of Scheme 1. The process of Scheme 2 is preferred. Step 1of Scheme 2 is an esterification of carboxylic acid XI with alcoholR⁴OH, in which R³ and R⁴ are as defined above, to generate ester XII. Inthis process, carboxylic acid XI is treated with alcohol R⁴OH,preferably a primary or secondary alcohol such as 2,2-dimethyl-propylalcohol, and an acid such as sulfuric acid, hydrochloric acid,methanesulfonic acid, toluenesulfonic acid, or camphor sulfonic acid,preferably sulfuric acid, in a solvent such as toluene, dichloromethane,or dichloroethane, preferably toluene, at a temperature of 0° C. toreflux temperature, preferably reflux temperature, for a period of oneto 24 hours, typically 4 hours, to provide ester XII.

[0109] In step 2 of Scheme 2, ester XII is treated with a base and theresulting ortho metallated species is trapped with a trialkylborate togive boronate ester XIII. In step 3 of Scheme 2, the boronate ester XIIIis hydrolyzed to the corresponding boronic acid XIV which is performedby methods known to those skilled in the art. In steps 2 and 3 of Scheme2, ester XII is treated with a metal amide base such as lithiumdiisopropylamide, lithium diethylamide, lithium2,2,6,6-tetramethylpiperidine, orbis(2,2,6,6-tetramethylpiperidino)magnesium, preferablylithiumdiisopropylamide, in the presence of a tri-(C₁-C₄ alkyl)borate, such astriisopropylborate, triethylborate, or trimethylborate, preferablytriisopropylborate, in an ethereal solvent, such as THF, diisopropylether, dioxane, or methyl tert-butyl ether, preferably THF, over atemperature range of about −78° C. to ambient temperature (20-25° C.),preferably about 0° C. After a period of 10 minutes to 5 hours,typically 1 hour, the reaction is quenched with aqueous acid to provideboronic acid XIV.

[0110] To facilite the handling of boronic acid XIV before proceeding tostep 4 of Scheme 2, the boronic acid XIV can be reacted with anaminodiol as illustrated in Scheme 3. In Scheme 3, boronic acid XIV isreacted with aminodiol XV, wherein R⁸, m and n are as defined above, ina solvent such as isopropanol, ethanol, methanol, hexanes, toluene, or acombination of the foregoing solvents, preferably isopropanol, at atemperature within the range of 0° C. to reflux temperature, preferablyambient temperature, for a period of 15 minutes to 10 hours, preferably10 hours, to provide the amine complex XVI. To proceed with step 4 ofScheme 2, amine complex XV is hydrolyzed to boronic acid XIV accordingto methods known to those skilled in the art. Such methods include theuse of aqueous acid, such as hydrochloric acid.

[0111] Step 4 of Scheme 2 is a Suzuki coupling between boronic acid XIVand chromanol VI to form the biaryl bound of IX. In this process, amixture is prepared containing boronic acid XIV, chromanol VI, apalladium catalyst, such as tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), palladium(II) acetate,allylpalladium chloride dimer, tris(dibenzylideneacetone)dipalladium(0),or 10% palladium on carbon, preferablytetrakis(triphenylphosphine)palladium(0), a base or fluoride salt, suchas sodium carbonate, triethylamine, sodium bicarbonate, cesiumcarbonate, tripotassium phosphate, pottasium fluoride, cesium fluoride,sodium hydroxide, barium hydroxide, or tetrabutylammonium fluoride,preferably sodium carbonate, and a solvent such as toluene, ethanol,dimethoxyethane, optionally containing water, preferably toluenecontaining water. In chromanol VI, which is prepared according to Scheme1, X′, which is attached at position 6 or 7 of the chroman ring,represents a halide or C₁-C₄ perfluoroalkylsulfonate, preferablybromide, iodide, or trifluoromethanesulfonate. The mixture is stirred ata temperature of between ambient temperature and reflux temperature,preferably reflux temperature, for a period of about 10 minutes to about6 hours, preferably 1 hour, to provide biaryl IX.

[0112] In step 5 of Scheme 2, ester IX is hydrolyzed to provide thecarboxylic acid X as described above for step 7 of Scheme 1.

[0113] The present invention is illustrated by the following examples,but it is not limited to the details thereof. In the following examples,the term “ambient temperature” means a temperature within the range ofabout 20° C. to about 25° C.

EXAMPLE 1 (R)-4-Benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one

[0114] To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14mol) and 500 mg of 2,2′-dipyridyl as an indicator in tetrahydrofuran (9L) at −78° C. was added over 30 minutes a 2.5 M solution of BuLi inhexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture wasmaintained at less than −55° C. during the addition. The reactionmixture was cooled to −75° C. and hydrocinnamoyl chloride (950 g, 5.63mol) was added over 5 minutes. The reaction mixture was allowed to warmto 0° C., at which point the reaction mixture was judged to be completeby thin layer chromatography (hexanes/ethyl acetate, 2:1). The reactionwas quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water(3.6 L). The aqueous phase was separated and extracted with ethylacetate (3 L). The combined organic layers were washed with 5% aqueoussodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L),dried over magnesium sulfate, and concentrated in vacuo to approximately2 L of a viscous yellow suspension. This slurry was dissolved in ethylacetate (3 L), concentrated to a solid, and dissolved in ethyl acetateat 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooledto 10° C. resulting in the precipitation of solids which were stirred at10° C. for 30 minutes. The solids were collected by filtration, washedwith hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%)of (B)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellowneedles: ¹H NMR (300 MHz, CDCl₃) δ 7.14-7.33 (m, 10H), 4.66 (m, 1H),4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd,J=9.5, 13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203,746, 699 cm⁻¹; mp 102-104° C.

EXAMPLE 2

[0115][4R-[3(2R,3R)]]-4-Benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one

[0116] To a solution of(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1064 g, 3.44 mol)in dichloromethane (5.6 L) at −5° C. was added dibutylboron triflate(1133 g, 4.13 mol) over 20 minutes, followed by the addition oftriethylamine (719 mL, 5.16 mol) while maintaining a reactiontemperature of less than 5° C. This mixture was cooled to −70° C., and asolution of 4-bromo-2-fluoro-benzaldehyde (699 g, 3.44 mol) indichloromethane (2 L) was added over 30 minutes. The mixture was allowedto warm to −10° C. over 1 hour, at which point it was judged to becomplete by thin layer chromatography (hexanes/ethyl acetate, 2:1). Thereaction was quenched by adding potassium phosphate monobasic-sodiumhydroxide pH 7 buffer (3.5 L) over 30 minutes followed by methanol (1.8L) and 35% aqueous hydrogen peroxide (1.8 L) over 1.5 hours whilemaintaining a reaction temperature of less than 15° C. The organic layerwas separated, washed with saturated aqueous sodium bicarbonate (6.7 L),and diluted with anhydrous ethanol (4 L) and 25% aqueous sodiumbisulfite. The organic layer was separated, washed with water (4 L),dried over magnesium sulfate, and concentrated in vacuo giving 1818 g(103%—crude weight) of[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-oneas a very viscous amber-colored oil: ¹H NMR (400 MHz, CDCl₃) δ 7.46 (t,J=8.0 Hz, 1H), 7.16-7.32 (m, 10H), 6.94-6.96 (m, 2H), 5.35 (d, J=4.7 Hz,1H), 4.92-5.29 (m, 1H), 4.45-4.51 (m, 1H), 3.92 (m, 2H), 3.01-3.14 (m,3H), 2.83 (dd, J=3.1, 13.6 Hz, 1H), 2.05 (dd, J=10.0, 13.5 Hz, 1H); IR3460 (br), 1780, 1696, 1483, 1388, 1350, 1209, 1106, 1068, 877, 760,747, 701, 583, 512, 486 cm⁻¹.

EXAMPLE 3

[0117][4R-[3(2R,3R)]]-4-Benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-Methyl-2-pyrrolidinone Solvate

[0118] To a solution of(R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one(12.0 kg, 38.8 mol)in dichloromethane (180 L) at −70° C. to −80° C. was added titaniumtetrachloride (8.8 kg, 46.6 mol) over 30 minutes giving a thicksuspension which was stirred for an additional 30 minutes at −70° C. to−80° C. N,N,N′,N′-Tetramethylethylenediamine (17.6 L, 116.4 mol) wasadded over 30 minutes giving a more fluid reaction mixture.1-Methyl-2-pyrrolidinone (7.6 kg, 77.6 mol) was added, and the reactionmixture was stirred for 30 minutes, all while maintaining a reactiontemperature of less than −65° C. A solution of4-bromo-2-fluoro-benzaldehyde (7.9 kg, 38.8 mol) in dichloromethane (38L) was added over 30 minutes while maintaining a reaction temperature ofless than or equal to −68° C. The reaction mixture was allowed to warmto 20° C. over 8 hours at which point it was cooled to 10° C. andquenched with a solution of 5.0 kg of ammonium chloride in 11 L of waterinducing a white precipitate and an exotherm to 28° C. Celite®(12 kg)was added and the reaction mixture was stirred for 12 hours at 20° C.The reaction mixture was filtered, concentrated atmospherically to anoil, treated with hexanes (120 L), concentrated to approximately 50 L,slowly cooled to 0° C. and granulated for 24 hours. The crude product,24.3 kg, was isolated by filtration, combined with the crude productsfrom two similar reactions in 110 L of dichloromethane, treated with 320L of hexanes, concentrated atmospherically to a final volume ofapproximately 250 L (distillate temperature 65° C.), seeded withauthentic product, and slowly cooled with granulation over 18 hours at20° C. Filtration yielded 67.4 kg (94%) of[4R-[3(2R,3R)]]-4-benzyl-3-12-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate as a light tan granular solid: ¹H NMR(400 MHz, CDCl₃) δ 7.46 (t, J=8.0 Hz, 1H), 7.15-7.29(m, 10H), 6.94 (dd,J=1.9, 7.2 Hz, 2H), 5.34 (d, J=4.8 Hz, 1H), 4.91-4.96 (m, 1H), 4.44-4.49(m, 1H), 3.90-3.95 (m, 2H), 3.55 (bs, 1H), 3.37 (dd, J=7.2, 7.2 Hz, 2H),3.00-3.13 (m, 2H), 2.83 (s, 3H), 2.82 (dd, J=3.3, 13.3 Hz, 1H), 2.36(dd, J=8.2, 8.2 Hz, 2H), 1.97-2.06 (m, 3H); IR 3150 (br), 1776, 1695,1652, 1600, 1221, 1050, 996, 953, 875 cm⁻¹; mp 80-83° C.

EXAMPLE 4

[0119] (1R,2S)-2-Benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol

[0120] A 2 M solution of lithium borohydride in tetrahydrofuran (1.7 L,3.4 mol) was diluted with tetrahydrofuran (1.7 L) and cautiously treatedwith water (61 mL, 3.4 mol) over 15 minutes. This mixture was stirred atambient temperature until hydrogen evolution ceased (0.5 to 1 hour), andthen added to a solution of[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one(1.75 kg, 3.4 mol) in tetrahydrofuran (8.75 L) at 0° C. over 30 minutes.The resulting milky-white suspension was allowed to warm to ambienttemperature over 12 hours at which point it was judged to be complete bythin layer chromatography (hexanes/ethyl acetate, 2:1). The reactionmixture was cooled to 15° C. and quenched with water (5.25 L) over 15minutes and stirred an additional 10 minutes before adding 35% aqueoushydrogen peroxide (2.6 L) over 20 minutes. The reaction mixture wasstirred for 15 minutes and then diluted with ethyl acetate (5.3 L) andwater (4 L). The organic layer was separated and washed with water (5.3L), 5% aqueous sodium bisulfite (5.25 L), and 50% saturated aqueoussodium chloride (7.5 L). Peroxides were detected in the organic layer,so it was further washed with 5% aqueous sodium bisulfite (5 L) and 50%saturated aqueous sodium chloride (6 L). The organic layer wasconcentrated in vacuo to an oil, diluted with ethyl acetate (4 L) andhexanes (13 L), and washed with 1 N aqueous hydrochloric acid (6 times17 L) to remove the (R)-(+)-4-benzyl-2-oxazolidinone. The organic layerwas washed with saturated aqueous sodium bicarbonate (5.3 L), dilutedwith toluene (2 L), and concentrated in vacuo yielding 1138 g (98%) of(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diolas an oil:¹H NMR (400 MHz, CDCl₃) δ 7.47-7.51 (m, 1H), 7.33 (dd, J=1.9, 8.3 Hz,1H), 7.15-7.25(m, 4H), 7.04-7.06 (m, 2H), 5.39 (d, J=2.6 Hz, 1H), 3.77(dd, J=3.0, 10.7 Hz, 1H), 3.64 (dd, J=5.0, 10.8 Hz, 1H), 3.44 (bs, 1H),2.68 (dd, J=11.0, 13.8 Hz, 1H), 2.59 (dd, J=4.1, 13.9 Hz, 1H),2.15-2.20(m, 1H), 2.01 (bs, 1H); IR 3370 (br), 3269 (br), 1485, 1406,1213, 1033, 1021, 870, 700 cm⁻¹.

EXAMPLE 5 (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol

[0121] A 1 M solution of sodium bis(trimethylsilyl)amide intetrahydrofuran (6.55 L, 6.55 mol) was added over 20 minutes to asolution of(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (1975 g,5.82 mol) in dimethyl sulfoxide (9.88 L) at ambient temperature. Themixture was slowly heated to 60° C. under aspirator vacuum to displacethe tetrahydrofuran from the reaction mixture, and then heated at 60 to65° C. for 5 hours under aspirator vacuum at which point the reactionwas judged to be complete according to thin layer chromatography(hexanes/ethyl acetate, 2:1). The reaction mixture was cooled to ambienttemperature and quenched by adding water (10 L) followed by 1 N aqueoushydrochloric acid (10 L). The resulting tan suspension was filtered,washed with water (2 L), and dissolved in ethyl acetate (12 L). Thissolution was washed with water (two times 12 L), concentrated to a lowvolume, dissolved in isopropyl ether (4 L), and concentrated underatmospheric pressure at 50 to 60° C. to 1.0 L, at which point solidsbegan to precipitate. The resulting suspension was cooled to ambienttemperature, stirred for 12 hours, concentrated to one-half its volume,cooled to 0 to 5° C., and filtered giving 916 g (49%) of(3S,4R)-3-benzyl-7-bromo-chroman-4-ol as a white solid. The filtrate wasconcentrated to a dark oil (906 g), dissolved in isopropyl ether (1.5 L)at reflux, cooled to ambient temperature, stirred, and filtered yieldingan additional 82 g of solid. The filtrate was concentrated andchromatographed on silica gel (60-230 mesh) eluting with 3:1hexanes/ethyl acetate. Product-rich fractions were concentrated andrecrystallizedfrom isopropyl etheryielding an additional 82 g of solid.The total yield of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol was 1080 g(58%): ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.33 (m, 2H), 7.21-7.25 (m, 1H),7.15-7.19 (m, 3H), 7.06-7.09 (m, 2H), 4.44 (bs, 1H), 4.21 (dd, J=2.6,11.3 Hz, 1H), 3.97 (dd, J=4.5, 11.3 Hz, 1H), 2.68 (dd, J=6.5, 13.8 Hz,1H), 2.51 (dd, J=9.1, 13.8 Hz, 1H), 2.18-2.23 (m, 1H), 1.85 (d, J=4.3Hz, 1H); IR 3274 (br), 3181 (br), 1598, 1573, 1493, 1480, 1410, 1219,1070, 1052, 1023, 859, 700 cm⁻¹; mp 143.5-144.0° C.

EXAMPLE 6 (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol

[0122] To a solution of(1R,2S)-2-benzyl-1-(4-bromo-2-fluoro-phenyl)-propane-1,3-diol (preparedfrom 33.5 kg (54.8 moles) of[4R-[3(2R,3R)]]-4-benzyl-3-[2-benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-oxazolidin-2-one,1-methyl-2-pyrrolidinone solvate without isolation) in 185 L oftetrahydrofuran was added 12.9 kg (115 mol) of potassium tert-butoxide.The reaction mixture was heated at reflux for 4 hours at which point thereaction was found to be complete by thin layer chromatography(hexanes/ethyl acetate, 3:1). The reaction mixture was cooled to ambienttemperature, quenched with 170 L of water, diluted with 83 L of ethylacetate, and acidified to pH 5.3 (aqueous layer) with 7.5 L ofconcentrated hydrochloric acid. The organic layer was concentrated undervacuum to approximately 38 L of a slurry, diluted with 76 L of isopropylether, warmed to dissolve the solids, slowly cooled to 0° C., andgranulated at 0° C. for 12 hours. (3S,4B)-3-Benzyl-7-bromo-chroman-4-ol,5.1 kg of white solid, was isolated by filtration. The mother liquor waswashed with 4 L of saturated aqueous sodium chloride, concentrated to afinal volume of 57 L, and granulated at 0° C. for 12 hours affording a4.3 kg second crop of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

[0123] A second identical reaction mixture was quenched, diluted withethyl acetate, and acidified as described above. The organic layer wasdried over 10 kg of magnesium sulfate, concentrated atmospherically toapproximately 30 L of a slurry, diluted with 38 L of isopropyl ether,concentrated to approximately 57 L, slowly cooled, and granulated at 0to 10° °C. for 12 hours. (3S,4R)-3-Benzyl-7-bromo-chroman-4-ol, 8.7 kg,was isolated by filtration. The mother liquor was combined with themother liquor from the second crop from the first reaction, concentratedto an oil, solidified by cooling, granulated in 6 L of isopropyl etherat 20° C. for 12 hours and 0° C. for 2 hours, and filtered giving 6.3 kgof (3S,4R)-3-benzyl-7-bromo-chroman-4-ol after washing with coldisopropyl ether. The combined crops from both reactions were driedgiving 20.8 kg (59%) of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol.

EXAMPLE 7

[0124] (3S,4R)-(3-Benzyl-4-hydroxy-chroman-7-yl)-boronic Acid

[0125] To a solution of (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (377 g,1.18 mol) in tetrahydrofuran (5.6 L) at −75° C. was added a 1.48 Msolution of methyllithium in ether (1.6 L, 2.37 mol) over 45 minuteswhile maintaining a temperature of less than −65° C. The reactionmixture was stirred at less than −65° C. for 1 hour, followed by theaddition of a 2.5 M solution of butyllithium in hexanes (440 mL, 1.3mol) over 15 minutes. The reaction mixture was stirred at less than −65°C. for 1 hour, followed by the addition of a 1.0 M solution ofborane-tetrahydrofuran complex in tetrahydrofuran (5.9 L, 5.9 mol) over30 minutes. The reaction mixture was warmed to 0° C., quenched by addingwater (4.4 L), adjusted to pH 2 with 1 N aqueous hydrochloric acid (4L), and extracted with isopropyl ether (4 L). The aqueous layer wasextracted with isopropyl ether (4 L), and the combined organic layerswere washed with 0.5 N aqueous sodium hydroxide (7.2 L). The aqueouslayer was adjusted to pH 3 with 1 N aqueous hydrochloric acid (5.5 L)and extracted with ethyl acetate (5.4 L and 2.7 L). The combined ethylacetate layers were dried over magnesium sulfate, and concentrated invacuo yielding 304.5 g (91%) of(3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronicacid as a yellow foam:¹H NMR (300 MHz, CDCl₃) δ 7.35-7.00 (m, 8H), 4.42 (d, J=4.1 Hz, 1H),4.19 (d, J=11 Hz, 1H), 3.90 (m, 1H), 2.68 (dd, J=6.2, 13.8 Hz, 1H), 2.47(m, 1H), 2.15 (m, 1H); IR 3330 (br), 1413, 1348, 1320, 1211, 1025, 749,730, 700 cm⁻¹.

EXAMPLE 8

[0126](3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid Ethyl Ester

[0127] A mixture of ethyl 2-iodo-4-trifluoromethyl-benzoate (723 g, 2.1mol), (3S,4R)-(3-benzyl-4-hydroxy-chroman-7-yl)-boronic acid (627 g, 2.2mol), potassium fluoride (366 g, 6.3 mol), 10% palladium on carbon (157g, 50% water wet), and anhydrous ethanol (6.27 L) was heated at refluxfor 3 hours at which point thin layer chromatography (toluene/aceticacid, 5:1) indicated the reaction to be complete. The reaction mixturewas diluted with isopropyl ether (8 L), filtered through Celite® andwashed with 10% aqueous sodium bicarbonate (1.5 L). The aqueous layerwas separated and extracted with isopropyl ether (3 L). The combinedorganic layers were washed with water (6 L), dried over magnesiumsulfate, and treated with Darco®G-60 (1.0 kg) and silica gel (1 kg,70-230 mesh) at ambient temperature. This mixture was filtered through apad of silica gel (70-230 mesh) and concentrated in vacuo to 922 g ofdark oil. This oil was diluted with ethyl acetate (1 L) and filteredthrough a column of silica gel (2 kg) eluting with ethyl acetate givinga light amber solution which was concentrated to afford 897 g (92%) of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacidethyl ester as a light amber oil: ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d,J=8.1 Hz, 1H), 7.63-7.67 (m, 2H), 7.18-7.38 (m, 6H), 6.91 (dd, J=1.8,7.8 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.55 (bs, 1H), 4.25 (dd, J=2.7,11.2 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 4.00 (ddd, J=1.0, 4.5,11.2 Hz,1H), 2.75 (dd, J=6.4, 13.9 Hz, 1H), 2.56 (dd, J=9.3, 13.8 Hz, 1H), 2.26(m, 1H), 1.93 (d, J=4.3 Hz, 1H), 1.09 (t, J=7.2 Hz, 3H); IR 3307 (br),3216 (br), 1734, 1339, 1298, 1247, 1191, 1175, 1118, 1097, 1050 cm⁻¹.

EXAMPLE 9

[0128](3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid

[0129] A mixture of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid ethyl ester (897 g, 1.93 mol) and 10% aqueous sodium hydroxide (980mL, 2.72 mol) in isopropyl alcohol (9 L) was heated at reflux for 6hours, cooled to ambient temperature, and stirred for 12 hours. Thereaction mixture was diluted with water (13.5 L), hexanes (9 L), andisopropyl ether (4.5 L). The aqueous layer was separated and extractedwith hexanes (9 L) and isopropyl ether (4.5 L), adjusted to pH 2 with 2N aqueous hydrochloric acid, and extracted with ethyl acetate (8 L and 4L). The combined ethyl acetate extracts were washed with water (6 L),dried over magnesium sulfate, and concentrated in vacuo to a dark amberoil which was diluted with toluene (2 L) and concentrated again to anoil. The oil was dissolved in toluene (4.2 L) at 60° C., and hexanes(8.8 L) were added at a rate to maintain a temperature of greater than50° C. The tan solids which precipitated upon slowly cooling to ambienttemperature over several hours were filtered and washed with 2:1hexane/toluene (2 L). These solids were dissolved in toluene (5 L) at60° C., treated with Darco®G-60, filtered, washed with toluene, andconcentrated in vacuo to approximately 4.0 L. This mixture was heated to50-60° C., treated drop-wise with hexanes (8.6 L), cooled, andgranulated at 5° C. for 1 to 2 hours. The resulting solids werefiltered, washed with 2:1 hexanes/toluene (2 L), and the wet cake wasstirred with hexanes (4 L) at reflux for 30 minutes. This mixture wascooled to ambient temperature, granulated for 1 hour, filtered, and theresulting solids were dried under vacuum overnight to provide 450 g(55%) of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacidas an off white solid: ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=8.1 Hz, 1H),7.66 (dd, J=1.1, 8.1 Hz, 1H), 7.63 (s, 1H), 7.15-7.32 (m, 6H), 6.89 (dd,J=1.7, 7.9 Hz, 1H), 6.85 (d, J=1.7 Hz, 1H), 6.1 (bs, 2H), 4.50 (d, J=4.3Hz, 1H), 4.18 (dd, J=2.7, 11.2 Hz, 1H), 3.94 (dd, J=4.6, 11.0 Hz, 1H),2.74 (dd, J=6.1, 13.8 Hz, 1H), 2.51 (dd, J=9.4, 13.9 Hz, 1H), 2.22 (m,1H); IR 3454, 3218 (br), 1699, 1431, 1337, 1299, 1275, 1258, 1191, 1178,1135, 1123, 700 cm⁻¹; mp 142° C.

EXAMPLE 10

[0130] 4-Trifluoromethyl-benzoic Acid 2,2-Dimethyl-propyl Ester

[0131] To a suspension of 4-trifluoromethylbenzoic acid (75.0 g, 394mmol) and 2,2-dimethyl-propyl alcohol (70.5 g, 800 mmol) in toluene (500mL) was added concentrated sulfuric acid (3.0 mL). The mixture wasstirred at reflux for 4 hours, cooled to room temperature, poured intosaturated aqueous sodium carbonate (250 mL) and the layers wereseparated. The organic layer was washed with saturated aqueous sodiumcarbonate (250 mL), and brine (100 mL), and was concentrated to give4-trifluoromethyl-benzoic acid, 2,2-dimethyl-propyl ester (102 g, 99%yield) as a yellow liquid: R_(f): 0.66 (ethyl acetate/hexanes 25/75); IR2932, 1727, 1327, 1280, 1133, 1066, 862, 775, 704 cm⁻¹; ¹H NMR (400 MHz,CDCl₃) δ 8.16 (d, J=7.9 Hz, 2H), 7.70 (d, J=8.1 Hz, 2H), 4.04 (s, 2H),1.04 (s, 9); ¹³C NMR (100 MHz, CDCl₃) δ 26.51, 31.61, 74.72, 123.63 (q,J=272.7HZ), 125.4, 129.9, 133.7, 134.35 (q, J=31.7 Hz), 165.35.

EXAMPLE 11

[0132] 2-(2,2-Dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronicAcid

[0133] To a solution of 4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester (4.225 g, 16.23 mmol) in tetrahydrofuran (40mL) was added triisopropylborate (9.00 mL, 39.0 mmol). The solution wascooled to −78° C. and lithium diisopropylamide (12.0 mL of a 2.0 Msolution in tetrahydrofuran/heptane, 24.0 mmol) was added dropwise over5 minutes. The red solution was stirred for 30 minutes, warmed to 0° C.,and quenched by the slow addition of 1 N hydrochloric acid (50 mL). Themixture was allowed to warm to room temperature, stirred for 30 minutesand added to hexanes (200 mL). The layers were separated and the organiclayer was washed successively with 2N hydrochloric acid (two times with100 mL), water (100 mL), and brine (50 mL). The organic extracts weredried over magnesium sulfate, filtered, and concentrated to an oil. Thecrude product was crystallized from heptane (40 mL) to provide2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid(3.037 g, 62% yield) as a white solid: mp=159-160° C.; IR 3377 (br),2963, 1703, 1371, 1308, 1171, 1131, 794, 709 cm⁻¹; ¹H NMR (400 MHz,DMSO/D₂O) δ 8.05 (d, J=8.1 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.66 (s,1H), 3.94 (s, 2H), 0.95 (s, 9H); ¹³C NMR (100 MHz, DMSO/D₂O) δ 26.69,31.69, 74.91, 125.29, 125.75, 128.30, 129.62, 131.98 (q, J=31.8 Hz),136.28, 142.68, 166.90.

EXAMPLE 12

[0134](3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid 2,2-Dimethyl-propyl Ester

[0135] A bi-phasic solution of2-(2,2-dimethyl-propoxycarbonyl)-5-trifluoromethyl-benzeneboronic acid(1.72 g, 5.66 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol(1.80 g, 5.63mmol), sodium carbonate (1.82 g, 17.2 mmol), andtretrakis(triphenyl-phosphine)palladium(0) (12 mg, 0.19 mol %) intoluene (15 mL) and water (9 mL) was stirred at reflux for 100 minutes.The reaction mixture was cooled to room temperature, poured into water(40 mL) and extracted with diisopropylether (75 mL). The organicextracts were washed with brine (50 mL), treated with DarcoO G-60, driedover magnesium sulfate, filtered through Celite®, and concentrated. Thecrude product was purified by chromatography on silica gel (ethylacetate/hexanes 20/80) to provide (3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoic acid2,2-dimethylpropyl ester as a white foam (2.35 g, 84% yield): R_(f):0.32 (ethyl acetate/hexanes25/75); IR 3407 (br), 2961, 1721, 1336, 1292,1252, 1172, 1134, 1110, 1022, 848, 749 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ7.90 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.63 (s, 1H), 7.19-7.37(m, 6H), 6.88-6.93 (m, 2H), 4.53 (t, J=4.4 Hz, 1H), 4.22 (dd, J=11.2,2.5 Hz, 1H), 3.99 (dd, J=11.2, 3.3 Hz, 1H), 3.78 (s, 2H), 2.73 (dd,J=13.8, 6.3 Hz, 1H), 2.54 (dd, J=13.6, 9.4 Hz, 1H), 2.20-2.80 (m, 1H),1.81 (d, J=5.2 Hz, 1H), 0.74 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 26.64,30.96, 34.62, 41.53, 64.76, 67.42, 75.33, 116.77, 121.07, 122.97,124.13, 126.44, 127.50, 127.54, 128.45, 128.60, 128.92, 129.11, 130.25,130.31, 139.08, 141.69, 142.03, 154.44, 168.14.

EXAMPLE 13

[0136](3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid

[0137] A solution of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid 2,2-dimethyl-propyl ester (2.34 g, 4.69 mmol) in isopropyl alcohol(23 mL) was treated with 10% aqueous sodium hydroxide (2.3 mL, 6.4 mmol)and heated at reflux for 3 hours. The reaction mixture was cooled toambient temperature, poured into water (34 mL), and extracted withhexanes (23 mL) and isopropyl ether (13 mL). The aqueous layer wasseparated and extracted with hexanes (23 mL) and isopropyl ether (13mL), adjusted to pH 2 with 6N aqueous hydrochloric acid, and extractedwith ethyl acetate (two times 40 mL). The combined ethyl acetateextracts were washed with brine (40 mL), dried over magnesium sulfate,filtered and concentrated to a white foam which was recrystallized fromtoluene/hexanes. The resulting solids were filtered and washed withhexanes, and the wet cake was stirred with hexanes (20 mL) for 1 hour.The mixture was filtered, and the resulting solids were dried undervacuum to provide 1.01 g (50% yield) of(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=8.1 Hz, 1H),7.67 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), 6.91 (dd,J=7.9,1.7 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24(dd, J=11.2,2.7 Hz, 1H), 3.97 (dd, J=11.0,4.0HZ, 1H), 2.76 (dd, J=13.9,6.4 Hz, 1H), 2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).

EXAMPLE 14

[0138] 2-[1,3,6,2]Dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl Ester

[0139] To a solution of 4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester (35.8 g, 138 mmol) in tetrahydrofuran (250 mL)was added triisopropylborate (73.0 mL, 316 mmol). The solution wascooled to 0° C., lithium diisopropylamide (73.0 mL of a 2.0 M solutionin tetrahydrofuran/heptane, 146.0 mmol) was added dropwise over 20minutes, and the red solution was stirred for an additional 30 minutes.Hexanes (200 mL) was added followed by 1N hydrochloric acid (200 mL).The mixture was stirred for 10 minutes and poured into hexanes (200 mL).The organic layer was washed with 1 N hydrochloric acid (two times 150mL), and brine (100 mL). The organic extracts were dried over magnesiumsulfate, filtered, and concentrated to about 200 mL. Isopropyl alcohol(100 mL), and diethanolamine (15.95 g, 151.7 mmol) were added, and themixture was stirred at room temperature for 10 hours. The solids werefiltered and washed with a mixture of isopropyl alcohol (15 mL) andhexanes (30 mL) to provide2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester (37.83 g, 74% yield) as a white solid.mp=233-234° C.; IR 3077, 2963, 2862, 1722, 1480, 1467, 1371, 1331, 1298,1290, 1279, 1254, 1161, 1117, 1108, 1087, 1074, 995, 952, 862, cm⁻¹; ¹HNMR (400 MHz, CDCl₃) d 8.23 (s, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.52 (dd,J=7.9, 1.3 Hz, 1H), 6.33 (brs, 1H), 4.08-4.14 (m, 2H), 3.98 (s, 2H),3.93-3.98 (m, 2H), 3.42-3.50 (m, 2H), 2.88-2.94 (m, 2H), 1.02 (s, 9H);¹³C NMR (100 MHz, CDCl₃) 26.51, 31.69, 50.92, 63.33, 74.72, 123.94,128.59, 132.06, 139.61, 171.56.

EXAMPLE 15

[0140](3S,4R)-Dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoate

[0141] A mixture of2-[1,3,6,2]dioxazaborocan-2-yl-4-trifluoromethyl-benzoic acid2,2-dimethyl-propyl ester (7.04 g, 18.9 mmol) in toluene (45 mL) and 1.5N hydrochloric acid (45 mL) was stirred at room temperature for 45minutes. The aqueous layer was removed and sodium carbonate (2.73 g,25.8 mmol), (3S,4R)-3-benzyl-7-bromo-chroman-4-ol (5.47 g, 17.1 mmol),tetrakis(triphenylphosphine)palladium(0) (24.0 mg, 20.8 μmol), and water(20 mL) were added. The bi-phasic solution was stirred at reflux for 100minutes, cooled to room temperature, and poured into water (50 mL). Thelayers were separated, and the organic layer was treated withDarco®G-60, filtered, and concentrated. The crude ester was dissolved inisopropyl alcohol (80 mL) and 10% aqueous sodium hydroxide (8.0 mL) wasadded. The solution was heated at reflux for 3 hours, cooled to roomtemperature, poured into water (120 mL), and extracted with hexanes (80mL) and isopropyl ether (40 mL). The aqueous layer was washed withhexanes (80 mL) and isopropyl ether (40 mL), adjusted to pH 2 with 6 Nhydrochloric acid, and extracted with methyl tert-butyl ether (two times75 mL). The organic extracts were dried over magnesium sulfate,filtered, and concentrated. The crude product was dissolved in methyltert-butyl ether (40 mL), and dicyclohexylamine (4.10 mL, 20.6 mmol) wasadded. The mixture as stirred overnight, and the solid was filtered andwashed with methyl tert-butyl ether (20 mL) to afford(3S,4R)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoate(7.32 g, 70% yield): mp=209-210° C; IR 3307, 3025, 2939, 2858, 1626,1564, 1429, 1398, 1388, 1333, 1168, 1119, 903, 875, 846, 838 cm⁻¹; ¹HNMR (400 MHz, CDCl₃) δ 7.62 (d, J=7.7 Hz, 1H), 7.55 (s, 1H), 7.52 (d,J=7.9 Hz, 1H), 7.17-7.31 (m, 6H), 7.08 (dd, J=7.9, 1.7 Hz, 1H), 7.00 (d,J=1.7 Hz, 1H), 4.48 (d, J=4.4 Hz, 1H), 4.17 (dd, J=11.0,2.6 Hz, 1H),3.90 (dd, J=11.0, 5.0 Hz 1H), 2.74-2.79 (m, 3H), 2.50 (dd, J=13.8, 9.4Hz, 1H), 1.80-1.82 (m, 4H), 2.20 (brs, 1H), 1.68-1.70 (m, 4H), 1.56 (d,J=12.2 Hz, 2H), 1.00-1.26 (m, 10H). ¹³C NMR (100 MHz, CDCl₃) δ 24.70,24.73, 25.03, 28.94, 29.09, 34.75, 41.75, 52.64, 65.00, 67.57, 116.50,121.42, 122.59, 123.77, 126.38, 126.73, 128.03, 128.55, 129.06, 129.45,138.95, 139.16, 142.51, 144.20, 154.04, 173.85.

EXAMPLE 16

[0142](3S,4R)-2-(3-Benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicAcid

[0143] A mixture of(3S,4B)-dicyclohexylammonium-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoate(2.37 g, 3.89 mmol) in ethyl acetate (25 mL), and 1 N hydrochloric acid(25 mL) was stirred at room temperature for 1 hour. The mixture waspoured into ethyl acetate (20 mL) and the aqueous layer was removed. Theorganic layer was washed with water (six times 50 mL), dried overmagnesium sulfate, filtered, and concentrated to provide(3S,4R)-2-(3-benzyl-4-hydroxy-chroman-7-yl)-4-trifluoromethyl-benzoicacid (1.66 g, 100% yield): ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=8.1 Hz,1H), 7.67 (d, J=8.1 Hz, 1H), 7.64 (s, 1H), 7.18-7.36 (m, 6H), 6.91 (dd,J=7.9,1.7 Hz, 1H), 6.86 (d, J=1.7 Hz, 1H), 4.53 (d, J=4.2 Hz, 1H), 4.24(dd, J=11.2,2.7 Hz, 1H), 3.97 (dd, J=11.0, 4.0 Hz, 1H), 2.76 (dd,J=13.9, 6.4 Hz, 1H), 2.53 (dd, J=13.7, 9.3 Hz, 1H), 2.24-2.26 (m, 1H).

EXAMPLE 17

[0144][[3(2R,3R)]-4R,5S]-3-[2-Benzyl-3-(4-bromo-2-fluoro-phenyl)-3-hydroxy-propionyl]-4-methyl-5-phenyl-oxazolidin-2-one

[0145] To a solution of(4R,5S)-4-methyl-5-phenyl-3-(3-phenyl-propionyl)-oxazolidin-2-one (1.50g, 4.8 mmol) in dichloromethane (23 mL) at −70° C. was added titaniumtetrachloride (0.6 mL, 5.3 mmol) giving a yellow-orange solution whichwas stirred for minutes at −70° C.N,N,N′,N′-Tetramethylethylenediamine(2.2 mL, 15 mmol) was added over 10minutes giving a dark red reaction mixture which was stirred for 70minutes at −78° C. 1-Methyl-2-pyrrolidinone (0.90 mL, 9.7 mmol) wasadded dropwise, and the reaction mixture was stirred for 30 minutes at−70° C. A solution of 4-bromo-2-fluoro-benzaldehyde (0.990 g, 4.9 mmol)in dichloromethane (5 mL) was added dropwise while maintaining areaction temperature of less than or equal to −68° C. The reactionmixture was stirred at −70° C. for 60 minutes and then allowed to warmto 0° C. over 90 minutes, at which point it was quenched with 15 mL ofsaturated aqueous ammonium chloride and 1.2 g. of Celite®. This mixturewas stirred overnight at room temperature and filtered. The phases wereseparated and the organic phase was washed three times with water andonce with brine, dried over magnesium sulfate, and concentrated undervacuum to 2.76 g of an oil containing the title compound and 1.2equivalents of 1-methyl-2-pyrrolidinone: ¹H NMR (400 MHz, CDCl₃) δ 7.48(t, J=8.1 Hz, 1H), 7.09-7.34 (m, 12H), 5.35 (d, J=7.3 Hz, 1H), 5.32 (d,J=4.9 Hz, 1H), 4.89-4.92 (m, 1H), 4.51-4.55 (m, 1H), 3.65 (bs, 1H), 3.35(dd, J=7.1, 7.1 Hz, 2H), 3.03-3.06 (m, 2H), 2.81 (s, 3H), 2.34 (dd,J=8.1, 8.1 Hz, 2H), 1.95-2.03 (m, 2H), 0.40 (d, J=6.6 Hz, 3H).

What is claimed is:
 1. A process of preparing a compound of the formula

or the enantiomer of said compound, wherein in said compound of formulaX the R³-substituted benzoic acid moiety is attached at carbon 6 or 7 ofthe chroman ring; R¹ is —(CH₂)_(q)CHR⁵R⁶ wherein q is 0 to 4; each R²and R³ is independently selected from the group consisting of H, fluoro,chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl, phenylsulfonyl, and—S(O)1(C₁-C₆alkyl) wherein n is 0 to 2, and wherein said alkyl group,the alkyl moiety of said alkoxy and —S(O)_(n)(C₁-C₆ alkyl) groups, andthe phenyl moiety of said phenylsulfinyl and phenylsulfonyl groups areoptionally substituted by 1 to 3 fluoro groups; R⁵ is H, C₁-C₆ alkyl, orphenyl substituted by R²; R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀aryl, or 5-10 membered heteroaryl, wherein said aryl and heteroarylgroups are optionally substituted by 1 or 2 substituents independentlyselected from phenyl, R², and phenyl substituted by 1 or 2 R²; whichcomprises treating a compound of the formula

or the enantiomer of said compound of formula IX in the preparation ofthe enantiomer of said compound of formula X, wherein R¹, R², and R³ areas defined above, R⁴ is C₁-C₆ alkyl, and the benzoate moiety is attachedto position 6 or 7 of the chroman ring, with a base.
 2. The process ofclaim 1 wherein the compound of formula IX, or the enantiomer of saidcompound, is prepared by treating a compound of the formula

or the enantiomer of said compound of formula VII in the preparation ofthe enantiomer of said compound of formula IX, wherein R¹ and R² are asdefined in claim 1 and the boronic acid moiety is attached at position 6or 7 of the chroman ring, with a compound of the formula

wherein R³ and R⁴ are as defined in claim 1 and Z is halo or C₁-C₄perfluoroalkylsulfonate, in the presence of a base or fluoride salt anda palladium catalyst.
 3. The process of claim 2 wherein the compound offormula VII, or the enantiomer of said compound, wherein R¹ and R² areas defined in claim 2, is prepared by treating a compound of the formula

or the enantiomer of said compound of formula VI in the preparation ofthe enantiomer of said compound of formula VI, wherein R¹ and R² are asdefined in claim 2 and X is a halide and is attached at position 6 or 7of the chroman ring, with (1) C₁-C₄ alkyl lithium, and (2) a boratingagent.
 4. The process of claim 3 wherein the compound of formula VI, orthe enantiomer of said compound, wherein R¹, R² and X are as defined inclaim 3, is prepared by treating a compound of the formula

or the enantiomer of said compound of formula V in the preparation ofthe enantiomer of said compound of formula VI, wherein R¹, R² and X areas defined in claim 3 and X is attached at position 4 or 5 of the phenylring, and Y is halo or nitro, with a base, optionally in the presence ofadded copper salts.
 5. The process of claim 4 wherein the compound offormula V, or the enantiomer of said compound, wherein R¹, R², X and Yare as defined in claim 4, is prepared by treating a compound of theformula

or the enantiomer of said compound of formula IV in the preparation ofthe enantiomer of said compound of formula V, wherein R¹, R², X and Yare as defined in claim 4 and X is attached at position 4 or 5 of thephenyl ring, and X_(c) is a chiral auxiliary, with a hydride reducingagent.
 6. The process of claim 5 wherein the compound of formula IV, orthe enantiomer of said compound, wherein R¹, R², X, X_(c) and Y are asdefined in claim 5, is prepared by treating a compound of the formulaR¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are as defined above, with (1) aLewis acid, (2) a base, and (3) a compound of formula

wherein R², X and Y are as defined in claim 5 and X is attached atposition 4 or of the phenyl ring.
 7. The process of claim 5 wherein thecompound of formula IV, or the enantiomer of said compound of formulaIV, wherein R¹, R², X, X_(c) and Y are as defined in claim 5, isprepared by treating a compound of the formula R¹—CH₂C(O)—X_(c), whereinR¹ and X_(c) are as defined in claim 5, with (1) a titanium(IV) halide,(2) a base optionally followed by treatment with a donor ligand, and (3)a compound of formula

wherein R², X and Y are as defined in claim 5 and X is attached atposition 4 or of the phenyl ring.
 8. The process of claim 1 wherein thecompound of formula IX, or the enantiomer of said compound, wherein R¹,R², R³ and R⁴ are as defined in claim 1, is prepared by coupling acompound of the formula

or the enantiomer of said compound of formula VI in the preparation ofthe enantiomer of said compound of formula IX, wherein R¹ and R² are asdefined in claim 1 and X′, which is attached at position 6 or 7 of thechroman ring, is halo or C₁-C₄ perfluoroalkylsulfonate, with a compoundof the formula

wherein R³ and R⁴ are as defined in claim 1, in the presence of a baseor fluoride salt and a palladium catalyst.
 9. The process of claim 8wherein the compound of formula XIV wherein R³ and R⁴ are as defined inclaim 8, is prepared by hydrolyzing a compound of the formula

wherein R³ and R⁴ are as defined in claim 8, the dashed line indicates abond or no bond between the B and N atoms, n and m are independently 2to 5, and R⁸ is H or C₁-C₆ alkyl.
 10. The process of claim 9 wherein thecompound of formula XVI, wherein R³, R⁴ and R⁸ are as defined in claim9, is prepared by reacting a compound of formula

wherein R³ and R⁴ are as defined in claim 9, with a compound of formulaHO(CH₂)_(m)—N(R⁸)—(CH₂)_(n)OH, wherein n, m, and R¹ are as defined inclaim
 9. 11. The process of claim 8 wherein the compound of formula XIV,wherein R⁴ and R³ are as defined in claim 8, is prepared by hydrolyzinga compound of the formula

wherein R³ and R⁴ are as defined in claim 8 and R⁷ is C₁-C₆ alkyl. 12.The process of claim 11 wherein the compound of formula XIII, whereinR³, R⁴ and R⁷ are as defined in claim 11, is prepared by treating acompound of the formula

wherein R³ and R⁴ are as defined in claim 11, with a metal amide base inthe presence of tri-(C₁-C₆ alkyl)borate.
 13. The process of claim 1 andfurther comprising reacting the compound of formula X, or the enantiomerof said compound, wherein R¹, R², and R³ are as defined in claim 1, witha secondary amine of the formula NHR⁵R⁶, wherein R⁵ and R⁶ are asdefined in claim 1, to form an ammonium carboxylate of the formula

or the enantiomer of said compound of formula XVII when prepared fromthe enantiomer of said compound of the formula X, wherein R¹, R², R³, R⁵and R⁶ are as defined in claim
 1. 14. A process of preparing a compoundof the formula

or the enantiomer of said compound, wherein R¹ is —(CH₂)_(q)CHR⁵R⁶wherein q is 0 to 4; each R² is independently selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆alkyl) wherein n is 0to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and—S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁵ is H, C₁-C₆ alkyl, or phenyl substituted by R²;R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10 memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted by 1 or 2 substituents independently selected from phenyl,R², and phenyl substituted by 1 or 2 R²; X_(c) is a chiral auxiliary;and, R¹¹ is C₁-C₉ alkyl, C₂-C₉ alkenyl or phenyl substituted by Y in the2 position, X in the 4 or 5 position, and R² in one of the remainingpositions of the phenyl moiety, wherein Y is halo, nitro or C₁-C₄alkoxy, and X is a halide, which comprises treating a compound of theformula R¹—CH₂C(O)—X_(c), wherein R¹ and X_(c) are as defined above,with (1) a titanium(IV) halide, (2) a base optionally followed bytreatment with a donor ligand, and (3) less than 2 equivalents of acompound of the formula R¹¹C(O)H, wherein R¹¹ is as defined above,relative to the amount of said compound of formula R¹—CH₂C(O)—X_(c). 15.A compound of the formula

or the enantiomer of said compound, wherein R¹ is —(CH₂)_(n)CHR⁵R⁶wherein q is 0 to 4; each R² is independently selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆ alkyl) wherein n is0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxyand —S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁵ is H, C₁-C₆ alkyl, or phenyl substituted by R²;R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10 memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted by 1 or 2 substituents independently selected from phenyl,R², and phenyl substituted by 1 or 2 R²; X is a halo group and isattached at position 4 or 5 of the phenyl ring; and, Y is halo or nitro.16. A compound of the formula

or the enantiomer of said compound, wherein R¹ is —(CH₂)_(q)CHR¹R¹wherein q is 0 to 4; each R² is independently selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆ alkyl) wherein n is0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxyand —S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁵ is H, C₁-C₈ alkyl, or phenyl substituted by R²;R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10 memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted by 1 or 2 substituents independently selected from phenyl,R², and phenyl substituted by 1 or 2 R²; X′ is halo or C₁-C₄perfluoroalkylsulfonate and is attached at position 6 or 7 of thechroman ring.
 17. A compound of the formula

or the enantiomer of said compound, wherein R¹ is —(CH₂)_(q)CHR⁵R⁶wherein q is 0 to 4; each R² is independently selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆alkyl) wherein n is 0to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and—S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁵ is H, C₁-C₆ alkyl, or phenyl substituted by R²;R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10 memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted by 1 or 2 substituents independently selected from phenyl,R², and phenyl substituted by 1 or 2 R²; and, the boronic acid moiety isattached at position 6 or 7 of the chroman ring.
 18. A compound of theformula

or the enantiomer of said compound, wherein the benzoate moiety isattached at carbon 6 or 7 of the chroman ring; R¹ is —(CH₂)_(q)CHR⁵R⁶wherein q is 0 to 4; each R² and R³ is independently selected from thegroup consisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C—C₆ alkyl) wherein n is 0to 2, and wherein said alkyl group, the alkyl moiety of said alkoxy and—S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁴ is C₁-C₆ alkyl; R⁵ is H, C₁-C₆ alkyl, or phenylsubstituted by R²; R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl,or 5-10 membered heteroaryl, wherein said aryl and heteroaryl groups areoptionally substituted by 1 or 2 substituents independently selectedfrom phenyl, R², and phenyl substituted by 1 or 2 R².
 19. A compound ofthe formula

wherein R³ is selected from the group consisting of H, fluoro, chloro,C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl, phenylsulfonyl, and—S(O)_(n)(C₁-C₆ alkyl) wherein n is 0 to 2, and wherein said alkylgroup, the alkyl moiety of said alkoxy and —S(O)_(n)(C₁-C₆ alkyl)groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonylgroups are optionally substituted by 1 to 3 fluoro groups; R⁴ is C₁-C₆alkyl; and, R⁷ is C₁-C₆ alkyl.
 20. A compound of the formula

wherein R³ is selected from the group consisting of H, fluoro, chloro,C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl, phenylsulfonyl, and—S(O)_(n)(C₁-C₆ alkyl) wherein n is 0 to 2, and wherein said alkylgroup, the alkyl moiety of said alkoxy and —S(O)_(n)(C₁-C₆ alkyl)groups, and the phenyl moiety of said phenylsulfinyl and phenylsulfonylgroups are optionally substituted by 1 to 3 fluoro groups; and, R⁴ isC₁-C₆ alkyl.
 21. A compound of the formula

wherein the dashed line indicates a bond or no bond between the B and Natoms; n and m are independently 2 to 5; R³ is selected from the groupconsisting of H, fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy,phenylsulfinyl, phenylsulfonyl, and —S(O)_(n)(C₁-C₆ alkyl) wherein n is0 to 2, and wherein said alkyl group, the alkyl moiety of said alkoxyand —S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁴ is C₁-C₆ alkyl; and, R¹ is H or C₁-C₆ alkyl. 22.An ammonium carboxylate of the formula

or the enantiomer of said compound, wherein in said carboxylate offormula XVII the R³-substituted phenyl moiety is attached at carbon 6 or7 of the chroman ring; R¹ is —(CH₂)_(q)CHR⁵R⁶ wherein q is 0 to 4; eachR² and R³ is independently selected from the group consisting of H,fluoro, chloro, C₁-C₆ alkyl, C₁-C₆alkoxy, phenylsulfinyl,phenylsulfonyl, and —S(O)_(n)(C₁-C₆alkyl) wherein n is 0 to 2, andwherein said alkyl group, the alkyl moiety of said alkoxy and—S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; each R⁵ is independently H, C₁-C₆ alkyl, or phenylsubstituted by R²; each R⁶ is independently H, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, or 5-10 membered heteroaryl, wherein said aryland heteroaryl groups are optionally substituted by 1 or 2 substituentsindependently selected from phenyl, R², and phenyl substituted by 1 or 2R².
 23. A compound of the formula

or the enantiomer of said compound, wherein X is attached at position 4or 5 of the phenyl moiety; R¹ is —(CH₂)_(n)CHR⁵R⁶ wherein q is 0 to 4;each R² is independently selected from the group consisting of H,fluoro, chloro, C₁-C₆ alkyl, C₁-C₆ alkoxy, phenylsulfinyl,phenylsulfonyl, and —S(O)_(n)(C₁-C₆alkyl) wherein n is 0 to 2, andwherein said alkyl group, the alkyl moiety of said alkoxy and—S(O)_(n)(C₁-C₆ alkyl) groups, and the phenyl moiety of saidphenylsulfinyl and phenylsulfonyl groups are optionally substituted by 1to 3 fluoro groups; R⁵ is H, C₁-C₆ alkyl, or phenyl substituted by R²;R⁶ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, or 5-10 memberedheteroaryl, wherein said aryl and heteroaryl groups are optionallysubstituted by 1 or 2 substituents independently selected from phenyl,R², and phenyl substituted by 1 or 2 R²; X is halo; Y is halo or nitro;and, X_(c) is a chiral auxiliary.